The overall goal of the proposed Seattle Primary Infection Program (SeaPIP) will be to define features of acute HIV-1 infection important to conferring a long-term advantage in controlling HIV-1 infection. State-of-the-art immunologic and virologic technologies will be brought to bear to discern biological mechanisms underlying host control. Our immunology project will be focused on identifying virus-specific immune responses as they develop in the newly infected host, and the effector cells of the immune response that correlate with virologic control. Two virology projects are proposed. One will identify the earliest targets of host-imposed viral genome selection, the reservoirs of infection under HAART, and the influence of therapies and host responses on this residual core of HIV-1 infection. The second virology project will define the impact of mutational changes that occur in the viral infection process on viral fitness in different host cell environments. We will further integrate these studies by defining host immune responses and virologic properties as functions of the following: time of infection, the time post-infection that therapy is initiated, and the T cell changes and viral rebound detected upon interruption or discontinuation of therapy. Senior investigators with long-term collaborative records in the field of primary HIV infection have been assembled to integrate cutting edge immunological, virologic and bioinformatics technologies with clinical observations. In support of these efforts, the program will include an experienced Clinical Core that will mount an aggressive recruitment effort focusing on new enrollment of patients in the earliest stages of HIV infection, as well as continue to monitor a high priority subset of 25 of the 143 patients in active follow-up in our Primary Infection Clinic (PIC) Cohort. A Virology Core will be responsible for receiving and storing specimens, specimen processing, virus isolation in tissue culture, viral load measurements, and drug resistance mutation testing. Lastly, an Administrative Core will function to coordinate continuous interactions between the program components, including facilitating scientific coordination, data and specimen management, fiscal oversight, and support for regulatory compliance, as well as providing statistical support for all Projects and Cores.